This is an application for a NIA Independent Scientist Award (K02). The candidate, Jenny Hsieh, Ph.D. is an Assistant Professor in her sixth year on the Molecular Biology faculty at UT Southwestern Medical Center in Dallas. Throughout her career, Dr. Hsieh has established a strong record of publications (23 total; 14 from her independent laboratory, awards and funding from both federal (NIA), non-federal (Ellison Medical Foundation, Welch Foundation, CURE, ARPATP, CPRIT) sources, and mentoring. Since joining the UT Southwestern faculty in 2005, Dr. Hsieh has developed a unique research program with a focus on understanding the epigenetic mechanisms of adult neural stem cells in physiological and pathological contexts. However, increasing administrative and teaching obligations have hampered Dr. Hsieh's research progress, such that she is able to only devote 50% of her time on research. The receipt of a K02 award would remove or restrict these obligations, thus allowing Dr. Hsieh (1) to advance her work on basic mechanisms of adult neural stem cell self-renewal and differentiation; (2) to nurture a newly-developed collaboration on the role of new granule neurons in epileptogenesis; (3) to learn the principals and practice of cutting-edge techniques (biochemical purification, ChIP-seq and RNA-seq) from on campus colleagues; (4) to explore her newly-generated REST conditional knockout mice to better understand the transcriptional and epigenetic circuitry important for neuronal cell fate, in both physiological and pathological contexts, such as after seizure activity; (5) to generate sufficient data for a series of grant applications, and the time to prepare them: a competitive renewal application for her existing R01, a new NIA R01 application, and an additional small or exploratory grant application, also to NIA; (6) to spend more time mentoring and interacting with two graduate students, two postdoctoral fellows, two research associates, and one undergraduate student in her laboratory; and (7) to engage colaborators from both inside and outside the stem cel field in research on hippocampal neuroplasticity induced by seizure activity. The stability and protected time offered by this K02 award would ultimately support three new projects exploring the complex relationship between brain injury signals such as seizures, adult neural stem cells, and the hippocampal niche in which these resident stem cells proliferate and differentiate into new granule neurons. As such, these studies hold great potential to improve our understanding of the complex mechanisms by which seizure activity affect brain plasticity, and therefore may open new avenues for the treatment of epilepsy. These studies may also shed light on the developmental mechanisms controlling the neuronal lineage program which have the potential to further therapeutic approaches to an increasing number of neuropsychiatric disorders linked to neuronal loss or aberrant neuronal function, which may be of particular importance for maintaining cognitive function during aging. PUBLIC HEALTH RELEVANCE: Disease, degeneration or traumatic injury of the nervous system are among the greatest public health concerns in the United States and are generally considered irreparable, often causing catastrophic damage to the functional capacity of the individual. Now, however, characterization of neural stem cells residing within specific germinal centers of the brain and in cell culture raises hope that functional regeneration of nervous tissue may be feasible, if we learn to exploit adult neurogenesis for clinical benefit. The research proposal will lead to improved understanding of neural stem cell biology, possibly leading to the development of new drugs for repair and regeneration of the nervous system.